During the past 80 years, plant extracts of the European mistletoe Viscum album L. have been widely used for cancer treatment in European countries. Preclinical data suggest immunostimulatory and other immunomodulatory effects of this plant extract. In clinical practice, mistletoe extracts have been used in cancer patients as sole intervention or as adjunct to conventional cancer therapies. Clinical efficacy in the treatment of cancer is an area of active investigation, with inconclusive results to date, due in large part to the use of varying preparations, concentrations, study populations and regimens. Moreover, little is known about the toxicity of mistletoe and the potential for botanical and drug interactions between mistletoe extract and standard chemotherapeutic agents. Gemcitabine is an approved antimetabolite chemotherapeutic agent with demonstrated single agent efficacy in the treatment of a wide range of solid tumors. Because the metabolism and pharmacokinetics of gemcitabine are well characterized, it is a chemotherapeutic agent well suited for the study of botanical/drug interactions in cancer therapy. The goals of this study are to investigate in a two-step phase I dose escalation design the effect of a highly purified mistletoe extract on the pharmacokinetics, pharmacodynamics, and safety of gemcitabine. Pharmacokinetic toxicity profiles of gemcitabine in combination with mistletoe, neutrophil recovery, cytokine gene expression, and serum levels of markers of immune activation will be investigated in 40-50 patients with advanced solid tumors. The study aims at establishing a paradigm for the investigation of botanicals used in conjunction with standard cancer chemotherapy in complementary cancer medicine. The study completed accrual in July 2007 after enrolling 44 patients: 17 patients had colorectal cancer, 12 breast cancer, 8 pancreatic cancer and 4 NSCLC, respectively. Patients experienced 4 DLTs, including grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 acute renal failure and grade 3 cellulitis . The MTD for the combination regimen of mistletoe and gemcitabine was established at gemcitabine dose level 8: 1300 mg/ m2 and mistletoe 250 mg s.c. The study is now closed to accrual and data analysis is ongoing.